Field of the Invention
The present invention provides certain enantiomerically pure aminoalcohol esters of arylcycloalkylhydroxycarboxylic acids, and processes for their preparation and medicinal use.
Esters of arylcycloalkylhydroxy acids with cyclic alcohols containing a quaternary nitrogen represented by formula I 
comprising a hydroxycarboxylic acid component in which AR is an aromatic ring and in which R1 is a cycloaliphatic ring, and comprising an alcohol component in which the hydroxyl group is located on a dimethylpyrrolidinium ring (n=1) or dimethylpiperidinium ring (n=2) in which R2=R3 is a lower alkyl and in which A is a halide, have in some instances been described as spasmolytics. If the two radicals R2 and R3 are identical, compounds of formula I have two chiral centers. One of the centers can be assigned to the acid moiety and relates to the position labeled 2xe2x80x2, the second chiral center is located in the cyclic ring system at the position labeled 3. Since compounds of this structure accordingly have two chiral centers, four stereoisomers (3R,2xe2x80x2R; 3S,2xe2x80x2R; 3R,2xe2x80x2S and 3S,2xe2x80x2S) are possible in principle. To date, pure stereoisomers of the formula I compound have been neither isolated nor synthesized, nor have they been investigated pharmacologicallyxe2x80x94which is essential for the subject matter of the present patent application. The most important representative of the formula 1, which is also used in therapy, is glycopyrronium bromide (AR=phenyl, R1=cyclopentyl, R2=R3=methyl, n=1, A=Br). The international non-proprietary name glycopyrronium bromide refers to the racemic mixture of diastereomers, which, accordingly, contains all four stereoisomers.
The publications and patents that have hitherto been published deal either with the drug glycopyrronium bromide in the form of a mixture of stereoisomers (CAS 596-51-0), with erythro-(RN 59677-73-5) or threo-(RN 59677-70-2) configured racemates of the tertiary amino ester (CRN 131118-11-1), which can be considered as only representing an intermediate in the synthesis of the compounds of the formula 1, or with the mixture of stereoisomers of the analogous cyclohexyl derivative (R1=cyclohexyl) of the formula I (where n=1) (RN 101564-29-8). The publications quoted in Chemical Abstracts 80:53209h and 80:53214f describe the results of the analyses of the crystal structures of the compounds glycopyrronium bromide and hexapyrronium bromide which are in the form of mixtures of stereoisomers. The publications quoted in Chemical Abstracts 80:66587e, 80:66588f and 89.191258 describe the results of pharmacological investigations with the mixture of stereoisomers of the compound glycopyrronium bromide, or of combination products of this substance with neostigmine and pyridostigmine. The publications quoted in Abstracts 84:43164h and 85:32832u describe the partial separation of the mixture of stereoisomers by means of a crystallization with 5-nitroisophthalic acid and the study of the threo- or erythro-configured racemates already mentioned above by NMR. Here, the authors succeeded, starting from the mixture of stereoisomers (CRN 131118-11-1), only in separating the diastereomers into the two racemates, but they did not succeed in preparing the enantiomerically pure compounds. The publications quoted in Chemical Abstracts 96:219498m, 105:48928x, 113:158782t, 89:191258k and the European Patent EP 128886 A2 describe the results of studies on the chromatographic analysis of the mixture of stereoisomers of the compound glycopyrronium bromide and the preparation of the stationary phases used. A separation of the enantiomers or an isolation of the individual stereoisomers of the formula I is not reported in any of the above-mentioned publications. In all cases mentioned, HPL-chromatographic separation succeeded only at the stage of the diastereomers. Thus, the preparation of the enantiomerically pure compounds of the formula according to the present invention is not known from the prior art.
The pharmacological action of medicinal substances of formula I is based on their interaction-with muscarinic acetylcholine receptors (muscarine receptors). They are therefore referred to as m-cholinoceptor antagonists or parasympatholytics orxe2x80x94owing to their relaxing effect on smooth musclesxe2x80x94as neurotropic spasmolytics. The multifarious effects of the parasympatholytics include: acceleration of the heart rate, reduced secretion of tears, saliva, perspiration, and of the glands of the digestive tract, relaxation of the smooth muscles of the bronchi, the gastrointestinal tract, the bile ducts, the urethra and the urinary bladder, pupil dilation and impairment of accommodation. Quaternary spasmolytics, which include the compounds of the formula I, do not cross the blood-brain barrier and therefore have no central activity. Depending on the mode of administration, the desired and undesired effects of parasympatholytics vary. If these substances are used as spasmolytics, the reduced secretion of saliva or pupil dilation, for example, will be referred to as side effect.
Based on recent research, it is known that the structure of muscarine receptors is not uniform, but that the pharmacological effects can be attributed to interactions with at least four different muscarine receptor subtypes. On the one hand, their distribution in different organs varies and, on the other hand, different muscarine receptor subtypes having different functions are involved in some neuronal signal transduction cascades. Various effects or side effects can be attributed to interactions with the different receptor subtypes, so that high subtype specificity is one of the aims in the development of modern spasmolytics.
Glycopyrronium bromide is an active compound which has been established for a long time but which does not meet the requirements of a xe2x80x9cmodernxe2x80x9d therapeutic of this type. However, glycopyrronium bromide is not only a racemate but additionally a mixture of diastereomers in which, depending on the preparation process, the ratios of the individual isomers in the product can in fact vary. Such isomeric active compound mixtures may therefore show random subtype profiles, making targeted use difficult and provoking the occurrence of undesirable side effects.
It is accordingly an object of the invention to provide enantiomerically pure esters, as well as processes for their preparation and their therapeutic use, that overcome the above-mentioned disadvantages of the prior art racemates of this type.
With the foregoing and other objects in view, the present invention provides enantiomerically pure esters enantiomerically enriched to an enantiomeric purity of 90% minimum enantiomeric excess (ee) selected from the group consisting of the (3R,2xe2x80x2R)xe2x80x94, (3S,2xe2x80x2R)xe2x80x94, (3R,2xe2x80x2S)xe2x80x94 and (3S,2xe2x80x2S)-configured enantiomers of the formula I 
in which
R1 is a mono-, bi- or tricyclic, saturated or unsaturated C3-C9-cycloaliphatic radical which is unsubstituted or substituted by one or more C1-C6-alkyl, C2-C6-alkenyl and/or C2-C6-alkynyl radical(s) and/or by one or more of the halogen atoms fluorine, chlorine, bromine or iodine;
R2 is a C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl radical which is unsubstituted or substituted by one or more of the halogen atoms fluorine, chlorine, bromine or iodine;
R3 is a C1-C6-alkyl, C2-C6-alkenyl or C2C6-alkynyl radical which is unsubstituted or substituted by one or more of the halogen atoms fluorine, chlorine, bromine or iodine;
AR is an aromatic radical having 6 to 10 carbon atoms which can be substituted by one or more lower alkyl group(s) having 1 to 6 carbon atoms, trifluoromethyl group(s), cyano group(s), alkoxy group(s), nitrogroup(s), amino group(s) and/or one or more halogen atom(s)xe2x80x94identical to or different from one anotherxe2x80x94
or
a 5- to 6-membered heteroaromatic ring containing oxygen, sulfur and/or nitrogen as heteroatoms and to which a further aromatic radical can be fused and which can be unsubstituted or substituted by one or more lower alkyl group(s) having 1 to 3 carbon atoms, trifluoromethyl group(s), cyano group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or more halogen atom(s)xe2x80x94identical to or different from one another;
n is an integer 1, 2 or 3; and
A is an anion of a pharmacologically acceptable acid.
In accordance with an additional feature of the invention, there are provided processes for the preparation of these enantiomerically pure esters of formula I and their use as medicaments.
In accordance with a further feature of the invention, preference is given to compounds of the formula I in which
R1 is a mono- or bicyclic C5-C7-cycloalkyl radical which is unsubstituted or substituted by one or more C1-C3-alkyl, C2-C6-alkenyl or
C2-C6-alkynyl, radical(s) and/or by one or more halogen atom(s) such as fluorine, chlorine, bromine or iodine;
R1 is a mono- or bicyclic C5-C7-cycloaliphatic radical which is unsubstituted or substituted by one or more C1-C3-alkyl, C2-C6-alkenyl or C2-C6-alkynyl radical(s) and/or by one or more of the halogen atoms fluorine, chlorine, bromine or iodine;
R2 is a C1-C3-alkyl, C2-C4-alkenyl or C2-C4-alkynyl radical which is unsubstituted or substituted by one or more halogen atoms fluorine, chlorine, bromine or iodine;
R3 is a C1-C3-alkyl, C2-C4-alkenyl or C2-C4-alkynyl radical which is unsubstituted or substituted by one or more halogen atoms fluorine, chlorine, bromine or iodine;
AR is a C6-C10-aromatic radical or a heteroaromatic radical containing sulfur as heteroatom;
n is an integer 1 or 2; and
A is an anion of a pharmacologically acceptable mineral acid or of a carboxylic acid.
Special preference according to this invention is given to those enantiomerically pure esters of formula I in which
R1 is a cyclopentyl, a cyclohexyl or a norbornyl radical;
R2 is a methyl radical;
R3 is a methyl radical;
AR is a phenyl radical or thienyl radical;
n is an integer 1 or 2;
A is fluoride, chloride, bromide or iodide, and in which OH, AR and R1 are arranged clockwise when viewed looking toward the carboxyl group.
In accordance with this invention, xe2x80x9cenantiomerically purexe2x80x9d is defined in terms of xe2x80x9cenantiomeric excessxe2x80x9d (e.e.) which is calculated from the ratio of the difference between the amounts of the respective enantiomers present and the sum of these amounts (Rxe2x88x92S)/(R+S) and expressed as a percentage. To illustrate, a preparation containing 95% of one enantiomer and 5% of the opposite enantiomer has an enantiomeric excess (e.e.) of (95xe2x88x925)/(95+5)=90%. The enantiomerically pure esters of formula I according to this invention have an e.e. of at least 90%,preferably at least 96%. Enantiomerically pure esters of formula I according to this invention with an e.e. of at least 96% are especially preferred, and even greater preference among these is given to enantiomerically pure esters of formula I according to this invention with an e.e. of at least 97% and particularly with an e.e. of at least 98%.